4-148435364-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000901.5(NR3C2):c.1497T>C(p.Asp499Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.884 in 1,614,036 control chromosomes in the GnomAD database, including 631,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 60353 hom., cov: 32)

Exomes 𝑓: 0.88 ( 571222 hom. )

Consequence

NR3C2
NM_000901.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.787

Publications

35 publications found

Variant links:

Genes affected

NR3C2 (HGNC:7979): (nuclear receptor subfamily 3 group C member 2) This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NR3C2 Gene-Disease associations (from GenCC):

autosomal dominant pseudohypoaldosteronism type 1
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
pseudohyperaldosteronism type 2
Inheritance: AD, Unknown Classification: LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

NR3C2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 4-148435364-A-G is Benign according to our data. Variant chr4-148435364-A-G is described in ClinVar as [Benign]. Clinvar id is 256828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.787 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.899 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5 link	c.1497T>C	p.Asp499Asp	synonymous_variant	Exon 2 of 9	ENST00000358102.8	NP_000892.2	P08235-1B0ZBF6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8 link	c.1497T>C	p.Asp499Asp	synonymous_variant	Exon 2 of 9	1	NM_000901.5	ENSP00000350815.3		P08235-1

Frequencies

GnomAD3 genomes

AF:

0.890

AC:

135302

AN:

152054

Hom.:

60295

Cov.:

show subpopulations

Gnomad AFR

AF:

0.907

Gnomad AMI

AF:

0.725

Gnomad AMR

AF:

0.835

Gnomad ASJ

AF:

0.900

Gnomad EAS

AF:

0.857

Gnomad SAS

AF:

0.904

Gnomad FIN

AF:

0.915

Gnomad MID

AF:

0.939

Gnomad NFE

AF:

0.891

Gnomad OTH

AF:

0.891

GnomAD2 exomes

AF:

0.877

AC:

220532

AN:

251386

AF XY:

0.881

show subpopulations

Gnomad AFR exome

AF:

0.908

Gnomad AMR exome

AF:

0.775

Gnomad ASJ exome

AF:

0.903

Gnomad EAS exome

AF:

0.862

Gnomad FIN exome

AF:

0.914

Gnomad NFE exome

AF:

0.891

Gnomad OTH exome

AF:

0.876

GnomAD4 exome

AF:

0.884

AC:

1291708

AN:

1461864

Hom.:

571222

Cov.:

AF XY:

0.885

AC XY:

643531

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.903

AC:

30230

AN:

33480

American (AMR)

AF:

0.786

AC:

35156

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.901

AC:

23539

AN:

26136

East Asian (EAS)

AF:

0.835

AC:

33145

AN:

39700

South Asian (SAS)

AF:

0.900

AC:

77641

AN:

86258

European-Finnish (FIN)

AF:

0.913

AC:

48756

AN:

53412

Middle Eastern (MID)

AF:

0.924

AC:

5329

AN:

5768

European-Non Finnish (NFE)

AF:

0.885

AC:

984013

AN:

1111992

Other (OTH)

AF:

0.892

AC:

53899

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

10046

20092

30138

40184

50230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.890

AC:

135414

AN:

152172

Hom.:

60353

Cov.:

AF XY:

0.890

AC XY:

66200

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.907

AC:

37652

AN:

41514

American (AMR)

AF:

0.834

AC:

12756

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.900

AC:

3124

AN:

3472

East Asian (EAS)

AF:

0.856

AC:

4421

AN:

5162

South Asian (SAS)

AF:

0.906

AC:

4367

AN:

4822

European-Finnish (FIN)

AF:

0.915

AC:

9689

AN:

10590

Middle Eastern (MID)

AF:

0.935

AC:

273

AN:

292

European-Non Finnish (NFE)

AF:

0.891

AC:

60590

AN:

68006

Other (OTH)

AF:

0.893

AC:

1884

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

760

1520

2280

3040

3800

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.840

Hom.:

115014

Bravo

AF:

0.881

Asia WGS

AF:

0.897

AC:

3120

AN:

3478

EpiCase

AF:

0.895

EpiControl

AF:

0.898

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp499Asp in exon 2 of NR3C2: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 91.35% (6042/6614) o f Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs5525). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant pseudohypoaldosteronism type 1

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

1.1

(source)

DANN

Benign

0.56

PhyloP100

0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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4-148435364-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over